Certain substituted phenyl compounds as juvenile hormone mimics

ABSTRACT

Insect populations are controlled by treating an immature form of the insect with a novel compound possessing juvenile hormonelike activity. Such a compound is one having the formula   wherein Y is substituted phenyl.

United States Patent [1 1 Emmick [451 Sept. 2, 1975 CERTAIN SUBSTITUTED PHENYL COMPOUNDS AS JUVENILE HORMONE MIMICS [75] Inventor: Thomas L. Emmick, Greenfield.

Ind.

[73] Assignee: Eli Lilly and Company, Indianapolis,

Ind.

[22] Filed: July 3, 1974 211 Appl. No.1 485,484

[52] U.S. Cl. 424/282; 424/DlG. l2; 424/DIG. 8;

424/278 [51] Int. Cl. AOIN 9/28 [58] Field of Search 424/DIG. 12, 278, 282

[56] References Cited UNITED STATES PATENTS 3,453,362 7/1969 Cruickshank 424/84 3,563,982 2/l97l Bowers 260/3405 OTHER PUBLICATIONS Borkovec, A., insect Chemosterilants, Vol. V", (1966). P. 61-63.

Primary Examiner-V. D. Turner Attorney, Agent, or Firm-Leroy Whitaker; Everet F. Smith [5 7] ABSTRACT lnsect populations are controlled by treating an immature form of the insect with a novel compound possessing juvenile hormone-like activity. Such a compound is one having the formula wherein Y is substituted phenyl.

4 Claims, No Drawings CERTAIN SUBSTITUTED PHENYL COMPOUNDS to which is attached a thiophene, benzene or substi- AS JUVENILE HORMONE MIMICS tuted benzene ring. The development of specific species of insect polulations are controlled by treating im- CROSS'REFERENCE mature forms of specific species of insects with a This application is a division of my copending appli- 5 a u ati n-inhibiting amount of one of my comcation Ser. No. 187,890, filed Oct. 8, 1971, now US. pounds. The compounds are eflective when ingested by Pat, No, 3,825,661, whi h in turn is a continuation-inthe immature insect form or when the immature insect part of my then copending application Ser. No. form is contacted with the compound. 877,019, filed Nov. 14, 1969, now abandoned, which in turn is a continuation-in-part of then copending applieation Ser. No. 787,281, filed Dec. 26, 1968, now abandoned.

BACKGROUND OF THE INVENTION DESCRIPTION OF THE PREFERRED EMBODIMENT The compounds of my invention are those having the following formula This invention concerns a method for controlling insects with a series of compounds which exhibit juvenile Z Z Z hormonelike activity. More particularly, this invention I a is concerned with the control of insect populations 2 2 2 a using a series of compounds comprising a long carbon R R2 chain containing at least 11 carbon atoms to which is attached a thiophene, benzene or substituted benzene h i ring. each of R R and R is a C -C alkyl group;

It is well known to control insects by treating a metae h of Z Z Z and Z separately is hydrogen or morphic stage of the insect with a juvenile hormone to halogen, or Z and Z together or 2;, and Z toprevent passage of the insect to a subsequent metamorth represents oxygen or a carbomtwcarbon phic stage. As a result of such treatment the insect will bond, provided that at least one pair of Z and Z not achieve full maturity. The structure of two such or Z and Z is oxygen; and hormones, Juvenile Hormones l and ll, are shown be- Y i phenyl substituted by methylenedioxy or ethylow. lenedioxy.

A series of synthetically prepared compounds having Thus, for example, each of R R and R may be juvenile hormone-like activity are described in South such groups as methyl, ethyl, n-propyl, and isopropyl. African Pat. No. 67/5149. These compounds, like the It is to be understood that all R groups need not be the naturally occurring hormones, have a straight-chain same in a particular molecule but that each R can take carbon skeleton. This carbon skeleton is terminated by on a value independent of the others.

Such groups as ester halo and amino' It is to be understood that Z and 2 are related as are wigglesworth, J. Ins. Physzol. 9, 105 (1963), re- 23 and Z4 Taken Separately, each 2 may be hydrogen ported that dendrolasin exhibits some juvenile horor halogen Z2 and Z2 taken together may be an oxygen mone activity. Dendrolasin is a naturally-occurring atom to form an e oxy group. Z and Z may also be Compound Secmted y the mandibular gland of the taken separately or together in this same manner. Halo- Chcmically, it is y gens that may be employed include chlorine, bromine, nonadiene. fluorine, or iodine. Chlorine is preferred.

in the course of synthetic studies in the diterpene series Nasipuri et al., J. Chem. Soc., 1964, 2146, pre- Y represents substtued phenyl Such as methylenedioxyphenyl or 3,4-ethylenedioxyphenyl.

pared 9-( 3-methoxyphenyl )-2,6-dimethyl2,6- nonadiene by means of the Wittig reaction. There was The preferred compounds of my invention are those no suggestion that the compound possesses biological in which R,, R and R are methyl or ethyl, each Z sepactivity. arately is hydrogen or Z and Z together and Z and Z together are oxygen, and Y is 3 ,4- SUMMARY methylenedioxyphenyl or 3,4-ethylenedioxyphenyl. l have nowdiscovered a class of compounds having The trans isomers of the unsaturated compounds are juvenile hormonelike activity. My compounds compreferred over the cis isomers. Particularly preferred prise a hydrocarbon chain of at least 1 1 carbon atoms are those compounds having the following structures.

Some of the compounds of my invention may be prepared by a five-step synthesis starting with the proper cinnamic acid. Where practical, the cinnamic acid for use in my process is one substituted in the benzene ring with those substituents which are desired in the final product. It will be apparent to a skilled chemist that it will sometimes be necessary to introduce substituents onto the ring at some intermediate point in my synthesis. Such a procedure does not detract from my overall synthesis. By means of my process the cinnamic acid side chain is expanded to the side chain found in the product.

As the first step of my process it is necessary to hydrogenate the double bond in the cinnamic acid side chain. The hydrogenation of carbon-carbon double bonds is well known to those skilled in the art and may be accomplished in the presence of the proper hydrogenation catalyst. I have found a catalyst of palladium on carbon to work quite well in this hydrogenation step. The reaction may be conducted at a temperature within the range of to 100C. and preferably within the range of 40C. at a pressure of up to 100 psig. and preferably at 30-50 psig. This pressure is the initial pressure in the reaction vessel and will decrease as hydrogen is consumed unless additional hydrogen is added to the vessel. The addition of more hydrogen is not essential to the process.

In the second step of 'my process the carboxyl group of the phenylpropionic acid obtained by hydrogenation of the cinnamic acid is reduced to a hydroxymethyl group. Means for reducing a carboxyl group are also known to those skilled in the art. I prefer to use lithium aluminum hydride as the reducing agent in an inert'solvent such as diethyl ether. The acid may be added as a solid to a solution of the lithium aluminum hydride in the solvent. However, I have obtained better results when the acid is added continuously in solution in the solvent. The temperature is preferably kept below 50C. and still more preferably below about 35C. When ether is employed as the solvent the reaction proceeds readily at the reflux temperature.

The phenylpropanol obtained in the preceding step is next treated with a phosphorus trihalide to replace the hydroxyl group with halogen. This reaction proceeds readily upon the addition of the phosphorous trihalide to a solution of the alcohol in an inert solvent such as carbon tetrachloride. The reaction is a mildly exothermic one and the temperature may be allowed to rise during the addition period. At the completion of the addition of the phosphorous trihalide the reaction mixture is preferably heated at a temperature of 50 to 100C. for a brief time of from say 5 to 30 minutes to insure complete reaction. I prefer to use phosphorous tribromide in this step.

Reaction of the halide from Step 3 with triphenylphosphine results in the preparation of a phosphonium halide. This reaction is preferably conducted in an inert hydrocarbon solvent such as benzene, toluene, or xylene. The temperature to be employed depends upon the substituents present in the benzene ring of the propyl halide. Stability problems arise with certain members of the series if temperatures much above C. are used. The reaction does proceed at temperatures of around 80C. and no stability problems are encountered at this temperature. With stable materials reaction temperatures in excess of 80C. may be employed to increase the reaction rate.

The phosphonium halides obtained at this step in the process are key intermediates for the preparation of the final active products. These phosphonium halides are reperesented by the formula wherein Y has the values assigned above and X is halogen such as bromine or chlorine. Of particular interest are those phosphonium bromides wherein Y is mmethoxyphenyl, p-methoxyphenyl, 3 ,4- methylenedioxyphenyl, or 3,4-ethylenedioxyphenyl.

In the final step of the process the phosphonium halide from Step 4 is reacted with the appropriate ketone in the presence of a base in the well-known Wittig reaction. This reaction is preferably conducted in a solvent under nitrogen at a temperature of 0 to 50C. and preferably 10 to 30C. Bases that have been typically employed in the Wittig reaction include sodium hydride,

sodium amide, and butyllithium in such solvents as dimethyl sulfoxide'and benzene. 1 have obtained good results in my process with butyllithium in dimethyl sulfoxide. v

The ketone for use in this step of my process is one having the structure wherein R R and R have the values assigned above. Any known method may be used in preparing these ketones. One such method is described, for example, in South African Pat. No. 67/5149.

This method of preparing the compounds of my invention will be further illustrated by the following examples. It is to be understood that these examples are merely illustrative and are not intended to limit the scope of the invention in any manner.

EXAMPLE 1 EXAMPLE 2 To a suspension of 13.2 g. of lithium aluminum hydride in 500 ml. of anhydrous ether was added 45 g. of 3-(3,4-methylenedioxyphenyl)propionic acid, prepared as in Example 1, in small portions as a solid at room temperature with rapid stirring. Following addi tion, the reaction mixture was heated under reflux overnight. The reaction mixture was cooled to 0 to C. and 13.2 ml. of water, 13.2 ml. of percent sodium hydroxide solution, and 39.6 ml. of water were added in that order. After stirring at room temperature for one hour the mixture was filtered to remove salts EXAMPLE 3 To a solution of 41.2 g. of 3-(3,4-methylenedioxyphenyl )propyl alcohol in 66 ml. of carbon tetrachloride was added dropwise with stirring 34 g; of phosphorous tribromide over a 20-minute period. The reaction temperature rose to 45C. during this addition. The reac* tion mixture was then heated at C. for 10 minutes and poured onto 200 ml. of crushed ice. This heterogeneous mixture was separated and the aqueous portion was extracted with 400 ml. of carbon tetrachloride. The extract was combined with the organic layer from the reaction mixture and the combined fractions washed with saturated sodium bicarbonate solution and saturated sodium chloride solution in that order and dried over magnesium sulfate. After one hour the solution was filtered, thecarbon tetrachloride was removed under reduced pressure and the residue was distilled at 0.5 mm. of mercury at an overhead temperature of 1 16 to 119C. to give 32 g. of the desired 3-(3,4- methylenedioxyphenyl)propyl bromide.

EXAMPLE 4 A solution of 40 g. of 3-(p-methoxyphenyl)propyl bromide and 49.3 g. of triphenylphosphine in 500 ml. of benzene was heated under reflux under nitrogen for 96 hours. The solid which precipitated was removed by filtration. This solid weighed 40 g. The benzene was removed from the solution under reduced pressure and 250 ml. of o-xylene was added to the residue. This solution was heated under reflux an additional three days. The solid resulting from this reaction was recrystallized from benzene'hexane to yield an additional 35 g. of product. The 3-(p-methoxyphenyl)propyltriphenylphosphonium bromide product had a melting point of 158 to 161C.

Analysis: Calculated for C ,;H BrOP:C, 68.25; H, 5.72; Br, 15.62. Found: C, 67.96; H, 5.76; Br, 15.45.

Following the procedure of Example 4 the following additional phosphonium bromides were also prepared.

Compound Melting Point,C.

3-( m-methoxyphenyl )propyltriphenyltriphenylphosphonium bromide EXAMPLE 5 A solution of 0.071 mole of butyllithium in 32.2 ml. of hexane was added to 50 m1. of anhydrous dimethyl sulfoxide. Following the evolution of butane 35.0 g. of 3-( p-methoxyphenyl )propyltriphenylphosphonium bromide was added portionwise over a period of 10 minutes. The resulting deep red solution was stirred for two hours at room temperature under nitrogen. To the mixture was then added a solution of 9.0 g. of 6-methyl- 5-heptene-2-one in 10 ml. of dimethyl sulfoxide. Stirring at room temperature was continued for 16 hours following the addition of the ketone. The reaction mixture was diluted with 350 ml. of water and the mixture was extracted twice with ether. The ether solutions were combined, washed with water, washed with saturated aqueous sodium chloride solution, and dried over EXAMPLE 6 The procedure of Example was repeated employing the m-methoxyphenyl compound in place of the pmethoxyphenyl compound. The product was evaporatively distilled at 105C. and 40 microns pressure. The infrared and nuclear magnetic resonance spectra confirmed the product to have the expected structure VII.

Analysis: Calculated for C, H O: C, 83.66; H, 10.14. Found: C, 83.94; H, 10.11.

EXAMPLE 7 The procedure of Example 5 was repeated using the 3,4-dimethoxyphenyl compound in place of the pmethoxyphenyl compound. The product from this reaction was evaporatively distilled at 120C. and 40 microns pressure. The nuclear magnetic resonance spectra was that expected for the desired product IX.

Analysis: Calculated for C, H O C, 79.12; H, 9.75. Found: C, 79.34; H, 9.54.

EXAMPLE 8 The procedure of Example 5 was repeated employing the 3,4-methylenedioxyphenyl compound in place of the p-methoxyphenyl compound. The product was chromatographed over silica gel and then evaporatively distilled at 100 to 125C. and 60 to 80 microns pressure. Structure III was confirmed by nuclear magnetic spectroscopy.

Analysis: Calculated for c,,H ,o,= C, 79.37; H, 8.88. Found: C, 79.14; H, 8.62.

EXAMPLE 9 EXAMPLE 10 Example 8 was repeated using 3-methyl-3-octene- 7-one as the ketone. The product was purified by chromatography over silica gel and evaporatively distilled at 150C. and 150 microns. Structure V was confirmed by the nuclear magnetic resonance spectrum.

EXAMPLE 1 l 3-(3,4-Dihydroxyphenyl)propionic acid (50 g.) was added to a cool solution of 55 g. of potassium hydroxide in 200 ml. of water. To this solution was added 56.4 g. of 1,2-dibromoethane and the resulting mixture was heated under reflux with stirring for 90 minutes. The mixture was cooled, chloroform was added, the aqueous portion was acidified with concentrated hydrochloric acid, and the layers were separated. The chloroform solution was washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. After filtering, the bulk of the chloroform was removed at 40C. under reduced pressure, with the temperature being raised to 50C. to remove the last trace of chloroform. A nuclear. magnetic resonance spectrum confirmed that the desired 3-(3,4- ethylenedioxyphenyl)propionic acid had been obtained in high purity. The yield was 22 g.

EXAMPLE 1 2 The product from EXAMPLE 11 was treated with lithium aluminum hydride as described in Example 2. The desired 3-(3,4-ethylenedioxyphenyl)propyl alcohol was obtained in an 18 g. yield.

EXAMPLE 1 3 The alcohol from Example 12 was treated with phosphorous tribromide as described in Example 3. The yield of the desired 3-(3,4-ethylenedioxyphenyl)propyl bromide was 17.1 g. The structure was confirmed by the nuclear magnetic resonance spectrum.

EXAMPLE l4 3-( 3 ,4-Ethylenedioxyphenyl )propyltriphenylphosphonium bromide was prepared by treating the bromide from Example 13 with triphenylphosphine following a procedure similar to that of Example 4 except that the reaction mixture was stirred as a melt with no solvent at C. and 10 mm. pressure. The yield of product melting at -l98C. was 22 g. The structure was confirmed by the nuclear magnetic resonance spectrum.

EXAMPLE 15 The phosphonium bromide from Example 14 was treated as described in Example 5 to yield the desired 9-( 3 ,4-ethylenedioxyphenyl )-2 ,6-dimethyl-2 ,6- nonadiene (VI). The structure was confirmed by nuclear magnetic resonance spectroscopy.

EXAMPLE l6 3-Hydroxycinnamic acid was converted to 3- ethoxycinnamic acid in the following manner. A solution of 25 g. of 3-hydroxycinnamic acid, 10 g. of sodium hydroxide and 32 g. of ethyl bromide in 300 ml. of ethanol was heated under reflux for 16 hours. Water was added and the mixture was acidified to precipitate the free acid product which was collected by filtration. Approximately 8 g. was obtained. The alcohol was distilled from the filtrate under reduced pressure. The resulting solution was extracted twice with benzene. The benzene extracts were combined, washed with brine, dried over magnesium sulfate, and the benzene evaporated to yield about 17 g. of the ethyl ester. of 3- ethoxycinnamic acid.

The ester was treated as described in Examples 1-5 to obtain 9-( 3-ethoxyphenyl )-2,6-dimethyl-2 ,6- nonadiene. The structure was confirmed by nuclear magnetic resonance spectroscopy.

EXAMPLE 1 7 3-(3,5-Dimethoxyphenyl)propionic acid was treated as described in Examples 2-5 to obtain 9-(3,5- dimethoxyphcnyl )-2,6-dimethyl-2 ,6-nonadiene. The

dubtion of substituents before hydrogenation. The former procedure is illustrated by Example 1 1.

My compounds can also be prepared by a Grignard coupling of a properly substituted benzyl halide and an aliphatic halide such as geranyl chloride or octyl bromide. The Grignard reaction is a well-known method of coupling two halides together. The Grignard reagent may be prepared from either the benzyl halide or the aliphatic halide and then coupled with the other. The

following examples will illustrate this method of preparation.

EXAMPLE 1 8 A solution of 154.3 g. of geraniol in 1.25 l. of anhydrous tetrahydrofuran was cooled to 0C. To this solution maintained at 0C. was added dropwise with stirring a solution of one mole of butyllithium in hexane (about 440 ml.). After all the butyllithium had been added, 84 g. of solid lithium chloride was added in one portion. A solution of 190.5 g; of p-toluenesulfonyl chloride in 750 ml. of anhydrous tetrahydrofuran was then added dropwise at 0C. The mixture was stirred for one-half hour after addition. Approximately 2 I. of water was added'and the layers were separated. The aqueous phase was reextracted with 1 1. of ether and the organic fractions were combined, washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. After drying over magnesium sulfate the solvents were removed, having 180 g. of a yellow liquid. This liquid was distilled to yield 1 18 g. of geranyl chloride, boiling point 73-74C. at 3 mm. pressure. The structure was confirmed by nuclear magnetic resonance spectroscopy.

EXAMPLE 1 9 Benzyl magnesium chloride was prepared by the dropwise addition, under nitrogen, of a solution of 31.8 g. of benzyl chloride in 200 ml. of anhydrous ethyl ether to 6.1 g. of magnesium. Following the addition,

the reaction mixture was heated under reflux for one hour and then stored overnight under nitrogen at room temperature. The solution was then added dropwise with stirring at room temperature to a solution of 35 g. of geranyl chloride in 50 ml. of anhydrous ether and 100 ml. of hexamethylphosphoramide. When about twothirds of the benzyl magnesium chloride had been added, a salt precipitated. An additional 100 ml. of hexamethylphosphoramide was added and the reaction mixture was warmed slightly. Addition was resumed and continued until the yellow reaction mixture turned dark brown. Water, 400 ml., and 300 ml. of ether were added. Following acidification of the aqueous phase.

saturated aqueous sodium chloride solution. The solution was dried over magnesium sulfate and the ether removed under reduced pressure, leaving 43 g. of a mobile yellow liquid. Chromatography over silica gel using benzene-hexane for elution followed by evaporative distillation at 90C. and 20 microns pressure gave quite pure trans-2,6-dimethyl-9-pheny1-2,6-nonadiene. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Other compounds prepared by the Gringnard coupling reaction were trans-2,6-dimethyl-9-(3-tolyl)-2,6- nonadiene, trans-2,6 dimethy1-9-( 3-chloropheny1)-2,6- nonadiene, trans-2,6-dimethy1-9-(4-chlorophenyl )-2,6- nonadiene, and trans-2,6-dimethyl-9-(3,4-dichlorophenyl)-2,6-nonadiene.

Still others of the compounds to be used in the method of my invention may be prepared by a method I shall refer to as the dithiane route. This route is depicted by the following equations:

CH CH In thefirst step of the dithiane route an aldehyde is reacted with 1,3-propanedithiol to obtain the 1,3- dithiane. This is a well-known method of blocking carbonyl groups and a skilled chemist would have no difficulty in preparing the dithiane. The reaction is carried out at elevated temperature in the presence of an acidic agent such as p-toluenesulfonic acid. The water of reaction is continuously removed by any convenient means, such as azeotropic distillation. The use of an inert solvent, especially one that forms an azeotrope with water, facilitates the reaction. This step of the process will be illustrated by the following example.

EXAMPLE 20 To a mixture of 30 g. (0.2 mole) of 3,4-methylenedioxybenzaldehyde and 21.8 g. (0.2 mole) of 1,3- propanedithiol in 400 ml. of benzene was added 1.5 g. of p-toluenesulfonic acid. The mixture was heated under reflux for one hour with the water formed being collected in a Dean-Stark trap. The reaction mixture was filtered and washed successively with saturated aqueous sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution. After the solution had been dried over magnesium sulfate, the benzene was removed at 40C. under'reduced pressure. The light yellow solid which remained was recrystallized from a benzene-petroleum ether mixture. Recrystallization affored 38.5 g. of the desired 2-(3,4- methylenedioxyphenyl l ,3-dithiane, m.p. 9596C.

Analysis: Calculated for C H O S C, 54.97; H, 5.03. Found: C, 55.15; H, 5.02.

In the second step of the process the dithiane is reacted with a ehlorodiene in the presence of a base. This reaction is conducted in an inert solvent in the cold. Temperatures are preferably kept below C., and more preferably below l0C. Suitable solvents include tetrahydrofuran, dioxane, and the like. The solvent should be thoroughly dried and care should be taken to keep the reaction mixture free of water until the reaction is completed have found butyllithium to befa particularly good base for the reaction. at times, it may be desirable to include an amine such as diisopropylamine. This step will be further illustrated by the following examples.

EXAMPLE 2] A solution of 24 g. (0.1 mole) of 2-(3,4- methylenedioxyphenyl)-l ,3-dithiane in 200 ml. of THF (dried over Cal-l was placed under a nitrogen atmosphere and cooled to 30C. and 50 ml. of a 23 percent solution of n-butyllithium in hexane was added dropwise with stirring. The reaction mixture was stirred for 1.5 hours while maintaining the temperature below l0C. A solution of 17.3 g. of trans-l-chloro-3,7- dimethyl-2,6-octadiene in 100 ml. of THF (dried over Cal-l was then added dropwise with stirring. The reaction mixture was maintained at 0C. for 70 hours. After acidification to a pH of 6 the reaction mixture was poured into 600 ml. of water. The resulting heterogeneous mixture was extracted three times with petroleum ether, the extracts were combined, washed with saturated aqueous sodium bicarbonate solution, water, and brine, and dried over magnesium sulfate. After evaporation of the petroleum ether there was obtained 30 g. of a light yellow oil. Purification was achieved by chromatographing g. of the oil over 500 g. of silica gel using benzene as the eluent. Fourteen grams of the desired trans-2-(3,7-dimethyl-2,6-octadienyl)-2-(3,4- methylenedioxyphenyl)-1,3-dithiane was obtained. The structure was confirmed by nuclear magnetic resonance spectroscopy.

EXAMPLE 22 A solution of 4.5 g. (51 mmoles) of diisopropylamine in 100 ml. of THF (distilled from LiAlH was cooled to -30C. under an atmosphere of nitrogen. To this cold solution was added dropwise with stirring 23 ml. of a 24 percent solution of n-butyllithium in hexane. A solution of 11.0 g. (50 mmoles) of 2-(4-cyanophenyl)- l,3-dithiane in 50 ml. of THF was added dropwise with stirring at 25" to 30C. The reaction mixture was stirred at '20 to 40C. for two hours. Trans-l-chloro- 3,7dimethyl-2,6-octadiene (8.6 g., 50 mmoles) in 50 ml. THF was added dropwise with stirring at 30C. After the reaction mixture had been stirred for one hour at about 75C., it was poured into twice its volume of water. The aqueous phase was twice extracted with petroleum ether and the extracts were combined and washed successively with saturated aqueous so-' dium bicarbonate solution, water and brine. After drying over magnesium sulfate the petroleum ether was evaporated, leaving 16 g. of a light yellow oil. The oil was purified by chromatography over 400 g. of silica gel using benzene as the eluent. Ten grams of the desired trans-2-( 4-cyanophenyl -2-( 3 ,7-dimethyl-2,6- octadienyl)-l,3-dithiane was obtained pure as shown by nmr.

EXAMPLE 23 n-Butyllithium, 13 ml. of a 23 percent solution in hexane, was added dropwise with stirring to 13 ml. of dry dimethyl sulfoxide maintained under an atmosphere of nitrogen. The resulting LiCH SOC1-I was added dropwise with stirring to 7.0 g. (25 mmoles) of 2-,( 3-bromophenyl)-1,3-dithiane in 130 ml. of THF (dried over Cal-I maintained at 30C. under nitrogen. Stirring at 30C. was continued for two hours. T- rans-l-chloro-3,7-dimethyl-2,6-octadiene (4.3 g., 25 mmoles) in 30 ml. of THF was added at 30C. The mixture was stirred while being allowed to slowly warm to room temperature overnight. The mixture was poured into twice its volume of ice water and extracted with ether. the ether extract was washed with brine and dried over magnesium sulfate. Removal of the ether at 40C. under vacuum afforded 12 g. of an oil. Five grams of the oil was purified by chromatography over 100 g. of silica gel, eluting with 1:1 benzene-petroleum ether. Three grams of pure trans-2-(3-bromophenyl)-2- (3,7-dimethyl-2,6-octadienyl)-1,3-dithiane was obtained as confirmed by nmr.

In the third step of the dithiane route the dithiane ring is cleaved by reduction to leave. a methylene group. Care must be exercised to cleave the dithiane without reducing the double bonds in the octadiene chain. I have found Raney nickel to be well suited for this reduction. Those skilled in the art will recognize that there are other reducing agents that can perform this selective reduction. The reduction will be illustrated by Example 24.

EXAMPLE 24 A mixture of 5.0 g. (12.4 mmoles) of trans-2-(4- carboethoxyphenyl )-2-( 3 ,7-dimethyl-2,6-octadienyl 1,3-dithiane and 48 ml. of settled Raney nickel in 500 ml. of anhydrous ethanol was stirred at room temperaing 3.4 g. of a colorless oil. The oil was purified by chromatography over g. of silica gel, eluting with 1:1 benzene-petroleum ether. Three grams of spectroscopically (nmr) and gas chromatographically pure trans-4( 4,8-dimethyl-3 ,7-nonadienyl )benzoate was obtained.

Other compounds of formula D prepared in this manner were those in which Y is 3 ,4 methylenedioxyphenyl.

Those compounds wherein one or more of the Z groups is halogen may be obtained by the known procedure of adding a hydrogen halide to one or both of the double bonds in the side chain. This results in one Z of a pair being halogen, while the other is hydrogen. This procedure is illustrated by Example 25.

EXAMPLE 25 Hydrogen chloride was bubbled into 200 ml. of carbon tetrachloride at C. To this solution was added 2.0 g. of 2,6-dimethyl-9-(3,4-methylenedioxyphenyl)-2,6r nonadiene and the mixture was placed in a refrigerator at 0C. for several hours. Evaporation of the solvent under reduced pressure left 2.5 g. of a viscous oil. The nuclear magnetic resonance spectrum of the product showed only a trace of vinyl absorption indicating that the reaction had proceeded to virtual completion.

The epoxides of my invention can be prepared in the usual manner by the oxidation of the double bond with hydrogen peroxide or a per acid. However, I prefer to prepare the epoxides by way of the halohydrin. the ep oxide is obtained from the halohydrin by dehydrohalogenation using a mild base. This process will be further illustrated by the following examples.

EXAMPLE 26 A solution of 5.0 g. of 9-(3,4 methylenedioxyphenyl )-2 ,6 dimethyl-2 ,6-nonadiene (prepared as in Example 8) in 73 ml. of dimethoxyethane was prepared. To this solution was added 22 ml. of water and the resulting heterogeneous mixture was cooled to 0C. To the cooled mixture was added 3.6 g. of N-bromosuccinimide portionwise over a period of minutes. This reaction mixture was stirred overnight at room temperature in the dark. The dimethoxyethane was removed under reduced pressure at 40C. Ether was added to the resulting mixture and the layers were separated. The aqueous phase was reextracted with ether and the ether solutions were combined and washed with water and saturated aqueous sodium chloride solution. After drying over magnesium sulfate the ether was removed at reduced pressure leaving approxzene-hexane and a gradient to 100 percent benzene was begun immediately. The volume of each fraction collected was ml. Fractions 3] to 250 were com bined to give approximately 5 g. of product. This prod uct was placed on a column of 120 g. of florisil in hexane and elution with hexane was begun. None of the bromohydrin was eluted in the initial 120 fractions and a gradient to 1:1 benzene-hexane was begun. Fractions 221 to 460 were combined to give 4.5 g. of product. The nuclear magnetic resonance spectrum of this product indicated it to be a mixture with the desired bromohydrin and the epoxide being the major compo nents. This mixture was subjected to dehydrohalogenation without further purification.

EXAMPLE 27 The 4.5 g. of the mixture from Example 26 and 2.8 g. of anhydrous potassium carbonate were combined in 35 ml. of anhydrous methanol and the mixture was stirred at room temperature for one hour. The excess potassium carbonate was removed by filtration and the methanol was removed from the filtrate at reduced pressure. Water and ether were added to the residue, the layers were separated and the ether phase was washed with water and saturated aqueoussodium chloride solution. After drying over magnesium sulfate, the ether was removed at 40C. underreduced pressure. The crude product was chromatographed on 80 g of deactivated silica using benzene for elution. Fractions 14 through 40 were combined to. give 2 g. of the epoxide. The product was evaporatively distilled at C. and microns pressure. The nuclear'magnetic resonance spectrum was consistent with the structure for the expected 9-( 3 ,4-methylenedioxyphenyl )-2,6- dimethyl-2,3-epoxy-6nonene (X).

Analysis: Calculated for C H O C, 74.97; H, 8.39. Found: c, 74.23;H, 8.70.

Those compounds of my invention containing side chain unsaturation may be hydrogenated to reduce the side chain double bonds. That is, those compounds wherein Z and Z together and Z and 2., together form a carbon to carbon bond may be hydrogenated to obtain those compounds wherein either 2 or- 4 of the Z groups are hydrogen. this hydrogenation step is the hydrogenation of a carbon to carbon double bond as dis cussed in Step 1 of my process for preparing the unsaturated compounds of the invention from a cinnamic acid. Methods of hydrogenating double bonds are well known to those skilled in the art. I have found this hydrogenation to proceed readily employing a catalyst of 5 percent palladium on carbon in an inerthydrocarbon solvent. Equivalent hydrogenation procedures will be apparent to those skilled in theart. The hydrogenation of an unsaturated compound of my invention to obtain a-fully saturated compound of my invention will be illustrated by the following example.

EXAMPLE 28 To a solution of l g. of 9-( 3 ,4- methylenedioxyphenyl )-2,6-dimethyl-2,o-nonadiene (prepared as in Example 8) in 40 ml. of benzene was added 2.0 g. of a 5 percent palladium on carbon catalyst. Hydrogen was introduced into the reaction vessel to a pressure of 50 psig. This mixture was shaken at room temperature for 16 hours. The catalyst was re moved by filtration and the benzene was evaporated under reduced pressure to yield pure 9-(3,4- methylenedioxyphenyl )-2,6-dimethylnonane v( XI The structure was confirmed by nuclear magnetic resonance spectroscopy.

In a first demonstration of the ability of my compounds to inhibit the maturation of insects the compounds were applied topically to a metamorphic stage of four insect species. The compounds were applied in acetone solution at concentrations of 10 percent, 1 percent and 0.5 percent. One microliter of the acetone solution was applied to each test specimen. Ten test specimens were employed for each insect at each concentration and compared to ten acetone controls and ten zero controls. Approximately eight to ten days were required before results could be ascertained.

The insect species used in the test were Tenebrio molitor pupae; milkweed bug, fourth nymphal stage; wax moth, fifth larval stage; and Mexican bean beetle, fourth larval stage. At the completion of the test, each speciment was examined for the degree of juvenile and adult characteristics. The milkweed bug, wax moth, and Mexican bean beetle were assigned a numerical rating of 0 to 3 with 0 indicating no effect and 3 indicating the maximum effect or least adult development. Be cause of differences in morphology the Tenebrio rating scale was 0 to 4. In all cases a'rating .of 2 or higher means. that the insect is incapable of reproduction. The number of specimens in each rating classification are given. The results for the compounds tested are summarized in the following tables. In any test where the total of specimens reported is less than 10, those unreported died in some metamorphic stage. Such deaths indicate control, since the dead insects are not capable of reproducing.

3,4-EPOXY-3 ,7-DIMETHYL- l 3,4-METHYLENE- DlOXYPHENYl.)-7-DECENE Rating Insect I Conc.,% 0 l 2 3 4 acet. l0

cont. 9 l MWB l 2 8 i 0.5 2 5 2 acet. l0

cont. l0 WM 1 acet. l0

cont. l0

MBB I 10 acet. l()

cont. l0

3,4-EPOXY-3-M ETHYL-7-ETHYL- l O-( 3,4-METHYLENE- DIOXYPHENYL )-7-DECENE cont. [0

Additional compounds in this series were tested against one or two of the insect species and were shown to be active against such species. The results of these tests are summarized in the following tables.

2,3-EPOXY-2,6-DIM ETHYL-9-( 3,4-METHYLENE- DIOXYPHENYL )-6-NONENE Rating Insect Conc.,% O l 2 3 4 Tenebrio 10 10 acet. 7 3

cont l0 MWB l 7 ucet. 6 cont. NOT TESTED Various of the compounds of this invention have been tested against several insect species representing a number of insect orders to demonstrate their versatility and broad spectrum activity. since the test methods used are different for different insects, each insect test will be described separately.

Mosquito.

7,8-epoxy 4-ethyl-8-methyll 3,4-methylenedioxyphenyl )-3-decene was tested against Aedes aegypti mosquito larvae in aqueous solutions at concentrations of 10, 5, 2.5, 1.25 and 0.625 ppm. Ninety milliliters of each solution were placed in'a pint jar and 30 five-dayold mosquito larvae were added to each jar. Two tests were run at each concentration and control tests employing only solvent with no compound were also run. Food was added to each jar, the jars were covered with cloths, and maintained at 29C. until adults emerged in the control jars. The number of adults in the test jars was determined. The results 13 days after the test started are summarized in the following table.

The decene gave percent control at concentrations as low as 0.625 ppm. Live adults were observed in the control jars six days after the start of the test. There were never any live adults in the decene jars at any concentration.

Test compound was mixed with the rearing diet of houseflys at various levels. The prepared diet was then placed in an 8 oz. drinking cup. Three cups were prepared for each treatment level and three control cups. Housefly eggs (Musca domestica) were placed in each cup and they were maintained at 28C. for one week. Fifty pupae were then removed from each cup and placed in a petri dish. After the control pupae had emerged into adults, the percent emergence in each dish was recorded. The test compound was 7,8-epoxy- 4-ethyl-8-methyll 3 ,4-methylenedioxyphenyl )-3- decene. The results in terms of percent adult emergence are summarized in the following table.

Conc. Cup Cup Cup Comppm. 1 2 3 pound Decene 100 l 0 20 l0 I0 100 I00 100 l l 00 I00 I00 0. l l 00 100 l 00 Control l 00 I00 I 00 7 formed wings, 2 indicating a partially emerged adult,

and 3 indicating no evidence of emergence. The results for the other compounds are reported on a scale-of to 2 with 0 indicating a normal adult, -1 indicating apartially emerged adult and 2 indicating no evidence of emergence. I

Female aphids were placed on young squash plants and allowed to produce young for 24 hours. After 24 hours, all adult aphids were removed from the plants and the young were maintained on the plants for an additional 48-hour period. This gave an aphid nymph population having an age of 48 to 72 hours. To each nymph was applied 0.1 ml. of a percent, 1 percent, or 0.5 percent solution of 7,8-epoxy-4-ethyl-S-methyll-'( 3 ,4-methylenedioxyphenyl )-3-decene in acetone and the aphid nymphs were transferred to new squash plants and observed for possible effects. Ten nymphs were treated with each concentration and 10 were treated with acetone alone while 10 were not treated to serve as controls. After three days, all of the nymphs treated at the 10 percent and 1 percent concentrations were dead while nine of the ten treated at 0.5 percent concentration were dead. There was only one dead nymph treated with acetone alone and one dead nymph I in the nontreated controls.

The activity of my compounds has been demonstrated against a number of orders of insects including Coleoptera, Diptera, Orthoptera, I-Iemiptera, Homoptera, and Lepidoptera. Examples of insects which are members of the orders against which my compounds are active include bean beetle, Tenebrio, confused flour beetle, the corn root worm, potatoe beetle, sawtooth grain beetle, alfalfa weevil, carpet beetle, housefly, yellow-fever mosquito, blow fly, German cockroach, American cockroach, house cricket, grasshopper, milkweed bug, squash bug, kissing bug, assassin bug, bedbug, aphids, leafhoppers, spittle bug, wax moth, Southern cecropia, worm, cercropia, tobacco bug worm, and cotton boll worm. Because of the close relationship of insect species within a given order, it is to be expected that all species within the order will exhibit similar behavior toward any particular juvenile hormone or juvenile hormone mimic.

The degree of activity toward a particular insect may vary from compound to compound within my invention. However, it is to be expected that at sufficiently high rates of application all of the compounds will exhibit some activity, although perhaps slight, toward insects belonging to the six orders named above. Simple tests such as those described herein may be used to determine the degree of activity of any particular compound against any particular insect.

Isomerization around the double bonds of my compounds can, and does, occur. Unless a particular isomer is noted, the tests described above were conducted on.the mixture of isomers which were obtained in the synthesis of the compound. For example, I have found my products to contain approximately 59 percent of the cis isomer and 41 percent of the trans isomer when prepared by the Wittig reaction. This ratio might be changed by using different conditions such as a different base and a different solvent in the Wittig reaction. It is to be understood that the claims of this application cover all active isomers as well as active mixtures of isomers of compounds of my invention. In those compounds where the pure cis or trans isomer has been ob- .tained, both isomers have been found to exhibit some activity but in general the trans isomers are more active.

The compounds of this invention are active when ingested by the immature insect form or upon contact with the immature insect. This contact may be with the compounds in solid, liquid or vapor states. In general, these compounds are also systemically active, i.e., they may be applied to soil where they will be taken up by the roots of a plant and transported to the foliage which is eaten by the insect form.

The amount of compound needed for field control of insects will depend upon the particular compound being used and the particular insect being treated. In general, the compounds should be applied at a rate of from about 0.2 to about 8 pounds per acre. If more than one insect species is involved, it may be desirable to use a mixture of two or more compounds.

For application, my compounds are incorporated with carriers and adjuvants in accordance with known procedures. They may be formulated, for example, as sprays, dusts, granules, wettable powders or soil drenches. The formulation of such compositions is well known using suitable solids such as silica, fullers earth, chalk, talc, attapulgite clays, kaolin clays, inorganic carbonates, lime and other known solid carriers. These may be applied as dusts or wettable concentrates may be prepared by including dispersing and emulsifying agents. Liquid concentrates may be obtained using suitable liquid carriers such as xylene, kerosene, aromatic naphthas and other organic solvents. In general, the juvenile hormore mimic is included at a concentration of about 2-50 percent.

When concentrates are prepared for dilution with water they should contain about 1-15 percent of a wetting or emulsifying agent. A large number of such agents are available commercially and are well known to those skilled in the formulation of pesticides. Typical of the surface active agents employed in this manner are the alkyl and alkylaryl polyether alcohols, sulfated higher alcohols and polyether alcohols, alkyl and alkylaryl sulfonates and sulfates, fatty acid amides, polyvinyl alcohols and polyethylene oxides. Other suitable surface active agents are known to those skilled in the art.

It is'to be understood that other active ingredients may be included in the formulation and applied with my juvenile hormone mimics. Such other active ingredients include fertilizers, herbicides, fungicides, nematocides, and especially insecticides.

I claim:

1. A method for controlling the development of an insect species that is a member of an order selected from the group consisting of Coleoptera, Diptera, Or-

, .19 thoptera, Hemiptera, Homop tera and' Lepidoptera which comprises treating, by contact or ingestion, an immature form of the insect species with a maturationinhibiting amount of a compound having the formula wz, f .2 2 V Y CH2CH2CH$CH2 CH,-CH-?4R3 wherein each of R R and R is a C -C group;

each of Z Z Z and Z separately is hydrogen or halogen, orZ and Z together'or Z and 2 together represents oxygen or a carbon-to-carbon bond, provided that at least one pair of Z and Z or 2;, and Z is oxy- Y is phenyl substituted by methylenedioxy or ethylenedioxy.

- 2. The method as in claim 1 wherein each of R R and R5 is methyl; Z and Z together are a carbon to 

1. A METHOD FOR CONTROLLING THE DEVELOPMENT OF AN INSECT SPECIES THAT IS A MEMBER OF AN ORDER SELECTED FROM THE GROUP CONSISTING OF COLEOPTERA, DIPTERA, ORTHOPTERA, HEMIPTERA, HOMOPTERA AND LOPIDOPTERA WHICH COMPRISES TREATING BY CONTACT OR DIGESTION, AN IMMATURE FORM OF THE INSECT SPECIES WITH A MATURATION-INHIBITING AMOUNT OF A COMPOUND HAVING THE FORMULA
 2. The method as in claim 1 wherein each of R1, R2, and R3 is methyl; Z1 and Z2 together are a carbon to carbon bond; Z3 and Z4 together are oxygen; and Y is 3,4-methylenedioxyphenyl.
 3. The method as in claim 1 wherein each of R1 and R2 is methyl; R3 is ethyl; Z1 anD Z2 together are a carbon to carbon bond; Z3 and Z4 together are oxygen; and Y is 3,4-methylenedioxyphenyl.
 4. The method as in claim 1 wherein each of R1 and R3 is ethyl; R2 is methyl; Z1 and Z2 together are a carbon to carbon bond; Z3 and Z4 together are oxygen; and Y is 3,4-methylenedioxyphenyl. 